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Review
. 2015 Apr 2:8:181-8.
doi: 10.2147/DMSO.S82272. eCollection 2015.

Streptozotocin-induced type 1 diabetes in rodents as a model for studying mitochondrial mechanisms of diabetic β cell glucotoxicity

Affiliations
Review

Streptozotocin-induced type 1 diabetes in rodents as a model for studying mitochondrial mechanisms of diabetic β cell glucotoxicity

Jinzi Wu et al. Diabetes Metab Syndr Obes. .

Abstract

Chronic hyperglycemia and the corresponding glucotoxicity are the main pathogenic mechanisms of diabetes and its complications. Streptozotocin (STZ)-induced diabetic animal models are useful platforms for the understanding of β cell glucotoxicity in diabetes. As diabetes induced by a single STZ injection is often referred to as type 1 diabetes that is caused by STZ's partial destruction of pancreas, one question often being asked is whether the STZ type 1 diabetes animal model is a good model for studying the mitochondrial mechanisms of β cell glucotoxicity. In this mini review, we provide evidence garnered from the literature that the STZ type 1 diabetes is indeed a suitable model for studying mitochondrial mechanisms of diabetic β cell glucotoxicity. Evidence presented includes: 1) continued β cell derangement is due to chronic hyperglycemia after STZ is completely eliminated out of the body; 2) STZ diabetes can be reversed by insulin treatment, which indicates that β cell responds to treatment and shows ability to regenerate; and 3) STZ diabetes can be ameliorated or alleviated by administration of phytochemicals. In addition, mechanisms of STZ action and fundamental gaps in understanding mitochondrial mechanisms of β cell dysfunction are also discussed.

Keywords: diabetes; glucotoxicity; mitochondria; redox imbalance; streptozotocin; β cell.

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Figures

Figure 1
Figure 1
Chemical structure of streptozotocin.
Figure 2
Figure 2
Mechanisms by which diabetic hyperglycemia can impose glucotoxicity on β cells. Notes: The biochemical pathways listed can be upregulated or activated by chronic hyperglycemia. Importantly, all these pathways are eventually involved in elevated production of reactive oxygen species that are detrimental to β cell function. These pathways can be dissected by animal models of STZ diabetes. Abbreviations: STZ, streptozotocin; ROS, reactive oxygen species.
Figure 3
Figure 3
Glucose combustion is tightly coupled to insulin secretion in pancreatic β cells. Notes: The figure shown depicts the main pathways of glucose metabolism and mitochondrial ATP production. Glucose is first transported into β cells via GLUT2 transporters, followed by glycolysis, Krebs cycle, and oxidative phosphorylation that eventually make ATP from the combustion of glucose. The elevated ratio of ATP/ADP, driven by high blood glucose, closes the KATP channel and opens the calcium channel on the cell membranes. The influx of calcium triggers exocytosis of insulin granules and subsequent insulin release. Abbreviation: TCA, tricarboxylic acid.
Figure 4
Figure 4
Role of redox imbalance between NADH and NAD+ in β cell dysfunction. Notes: Under euglycemic condition, the balance between NADH and NAD+ is well maintained. However, under diabetic hyperglycemic condition, the balance between NADH and NAD+ is broken by several mechanisms such as NADH overproduction via the glycolytic and the polyol pathways and NAD+ depletion by poly ADP-ribosylase, sirtuins, and CD38. Albeit intensive studies in the field of diabetes, the role of complex I that makes NAD+ from NADH in this redox imbalance is unknown, so is the role of those enzymes making NADH from NAD+.
Figure 5
Figure 5
Scheme showing partial destruction of β cell population by STZ and reduction in β cell mass that induces insulin insufficiency and chronic hyperglycemia. Notes: While STZ-destructed β cells undergo necrosis and elimination by macrophages, the surviving or residual β cells are exposed to persistent hyperglycemia that can impair mitochondrial function in the residual β cell population. Abbreviation: STZ, streptozotocin.

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